2. Academic Validation
  3. Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening

Discovery of the first Mycobacterium tuberculosis MabA (FabG1) inhibitors through a fragment-based screening

  • Eur J Med Chem. 2020 Aug 15;200:112440. doi: 10.1016/j.ejmech.2020.112440.
Léo Faïon 1,  Kamel Djaout 2,  Rosangela Frita 2,  Catalin Pintiala 1,  Francois-Xavier Cantrelle 3,  Martin Moune 2,  Alexandre Vandeputte 2,  Kevin Bourbiaux 1,  Catherine Piveteau 1,  Adrien Herledan 1,  Alexandre Biela 1,  Florence Leroux 1,  Laurent Kremer 4,  Mickael Blaise 5,  Abdalkarim Tanina 6,  René Wintjens 6,  Xavier Hanoulle 3,  Benoit Déprez 1,  Nicolas Willand 1,  Alain R Baulard 2,  Marion Flipo 7
Affiliations

Affiliations

  • 1 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France.
  • 2 Univ. Lille, CNRS, Inserm, CHU Lille, Institut Pasteur de Lille, U1019 - UMR 9017 - CIIL - Center for Infection and Immunity of Lille, F-59000, Lille, France.
  • 3 Univ. Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1167 - RID-AGE - Risk Factors and Molecular Determinants of Aging-Related Diseases, F-59000, Lille, France; CNRS, ERL9002 - Integrative Structural Biology, F-59000, Lille, France.
  • 4 Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR 9004, 34293, Montpellier, France; INSERM, Institut de Recherche en Infectiologie de Montpellier, Montpellier, France.
  • 5 Institut de Recherche en Infectiologie de Montpellier (IRIM), Université de Montpellier, CNRS UMR 9004, 34293, Montpellier, France.
  • 6 Unité Microbiologie, Chimie Bioorganique et Macromoléculaire (CP206/04), Département RD3, Faculté de Pharmacie, Université Libre de Bruxelles, B-1050, Brussels, Belgium.
  • 7 Univ. Lille, Inserm, Institut Pasteur de Lille, U1177 - Drugs and Molecules for Living Systems, F-59000, Lille, France. Electronic address: [email protected].
PMID: 32505086 DOI: 10.1016/j.ejmech.2020.112440
Abstract

Mycobacterium tuberculosis (M.tb), the etiologic agent of tuberculosis, remains the leading cause of death from a single infectious agent worldwide. The emergence of drug-resistant M.tb strains stresses the need for drugs acting on new targets. Mycolic acids are very long chain fatty acids playing an essential role in the architecture and permeability of the mycobacterial cell wall. Their biosynthesis involves two fatty acid synthase (FAS) systems. Among the four enzymes (MabA, HadAB/BC, InhA and KasA/B) of the FAS-II cycle, MabA (FabG1) remains the only one for which specific inhibitors have not been reported yet. The development of a new LC-MS/MS based enzymatic assay allowed the screening of a 1280 fragment-library and led to the discovery of the first small molecules that inhibit MabA activity. A fragment from the anthranilic acid series was optimized into more potent inhibitors and their binding to MabA was confirmed by 19F ligand-observed NMR experiments.

Keywords

FabG1; Fragment; MabA inhibitors; Mycolic acid; Tuberculosis.

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